The overall objective of this project is to use genetic models of neoplastic disease in man to gain an increased understanding of the mechanisms of human tumorigenesis and the role of the cell surface in the origin and growth of tumors. The general approach will be to use methods proven useful in the study of virally transformed animal cells in tissue culture to study cultured cells from patients with inherited tumors. A number of biochemical changes in the cell surface membrane have been found in various types of virally transformed animal cells in culture. Among these are decreased amounts of gangliosides and glycolipids, decreased amounts of the glycosyltransferase enzymes that synthesize glycolipids and gangliosides, increased numbers of sialic acid residues bound to specific families of glycopeptides, increased amounts of sialyltransferases, and enhanced agglutinability of the tumor cells by lectins. There are a number of human diseases including neurofibromatosis, tuberous sclerosis, retinoblastoma, and Wilms' tumor in which tumors and growth abnormalities of various types are inherited as the primary abnormality. These have been largely neglected in cancer research but provide excellent genetic models of tumorigenesis. This project will use cultured tumor cells and cells at risk for becoming neoplastic from these patients and compare them with cultured control cells with respect to the biochemical membrane properties mentioned above. It will then be possible to see whether any abnormality found is inherited by examining members of the kindred. The project represents: 1) a test of current ideas about multi-stage mutation in tumorigenesis; 2) a test of the importance of cell surface changes in human tumors; and 3) a search for the inherited defect at the biochemical level in human inherited tumors and tumor syndromes.